Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies

  • ACS Med Chem Lett. 2014 Dec 8;6(2):173-7. doi: 10.1021/ml500424z.
Sergio Valente  1 ,  Veronica Rodriguez  1 ,  Ciro Mercurio  2 ,  Paola Vianello  3 ,  Bruna Saponara  4 ,  Roberto Cirilli  4 ,  Giuseppe Ciossani  5 ,  Donatella Labella  1 ,  Biagina Marrocco  1 ,  Giovanni Ruoppolo  6 ,  Oronza A Botrugno  3 ,  Paola Dessanti  3 ,  Saverio Minucci  7 ,  Andrea Mattevi  5 ,  Mario Varasi  3 ,  Antonello Mai  8
Affiliations
  • 1. Department of Drug Chemistry and Technologies, Sapienza University of Roma , P.le A. Moro 5, 00185 Roma, Italy.
  • 2. Genextra Group, DAC s.r.l. , Via Adamello 16, 20139 Milano, Italy.
  • 3. Dipartimento di Oncologia Sperimentale, IEO-European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy.
  • 4. Department of Therapeutic Research and Medicines Evaluation, Italian National Institute of Health , Via Regina Elena 299, 00161 Roma, Italy.
  • 5. Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
  • 6. Department of Sense Organs, Sapienza University of Roma , P.le A. Moro 5, 00185 Roma, Italy.
  • 7. Dipartimento di Oncologia Sperimentale, IEO-European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy ; Department of Biosciences, University of Milan , 20100 Milan, Italy.
  • 8. Department of Drug Chemistry and Technologies, Sapienza University of Roma , P.le A. Moro 5, 00185 Roma, Italy ; Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Roma , P.le A. Moro 5, 00185 Roma, Italy.
PMID: 25699146 DOI: 10.1021/ml500424z
Abstract

The pure four diastereomers (11a-d) of trans-benzyl (1-((4-(2-aminocyclopropyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate hydrochloride 11, previously described by us as LSD1 inhibitor, were obtained by enantiospecific synthesis/chiral HPLC separation method. Tested in LSD1 and MAO assays, 11b (S,1S,2R) and 11d (R,1S,2R) were the most potent isomers against LSD1 and were less active against MAO-A and practically inactive against MAO-B. In cells, all the four diastereomers induced Gfi-1b and ITGAM gene expression in NB4 cells, accordingly with their LSD1 inhibition, and 11b and 11d inhibited the colony forming potential in murine promyelocytic blasts.

Keywords
Epigenetics; leukemia; lysine-specific demethylase; stereoisomers; tranylcypromine.
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